Metabolic programming Part I COGS 163 Week 6 May 5, 2015 Janet - - PowerPoint PPT Presentation

Metabolic programming Part I

COGS 163 Week 6 May 5, 2015 Janet Tung and Miguel Wang

You are what your mom eats…?

 Does maternal diet matter?  What effects does it have?  How? When?  Are these effects

reversible?

www.stateofobesity.org 1990: 10-15% obese 2013: 35% obese Childhood obesity: 17% (tripled since 1980) Diabetes: 9.3% (29 million people)

Pregnancy rates of obesity and diabetes

 Maternal obesity: 15-40%  Maternal diabetes: 3-10%  Gestational diabetes: 7-18 %  In humans: offspring of obese, diabetic,

and hyperglycemic mothers

 Increased risk of metabolic disorders

Metabolic programming

What’s the mechanism?

Mechanism: Hypothalamic circuitry

Neonatal Insulin Action Impairs Hypothalamic Neurocircuit Formation in Response to Maternal High-Fat Feeding Vogt, et al., Cell (2014)

www.examiner.com

From Adena and Andrea’s presentation

Previous studies showed:

• Gross changes in hypothalamic

neurocircuits

• Differential neuropeptide

expression

• Altered hypothalamic neuronal cell

numbers

• Impaired formation of

hypothalamic axonal projections

Timing? Molecular mechanisms?

Developing a mouse model

 Differential developmental course than

humans Mouse:

 In utero: neuronal cells numbers are

determined

 Lactation: formation of functional

neuronal networks, including ontogeny

• f axonal projections and synaptic

connections

Experiment design: Timing of diet

Offspring 8-12 weeks Maternal Postnatal Maternal Pregestation, Prenatal

NC or HF NC NC HF HF NC HF

Results: timing

HFD during Lactation = Elevated serum insulin

Results: mechanisms

• 1. Markers of predisposition to metabolic disorders
• 2. Effects on hypothalamic circuitry
• 3. Axonal projections of ARC neurons to downstream sites
• 4. Role of insulin signaling in offspring predisposition to metabolic disorders
• 5. Can predisposition be ameliorated by eliminating POMC insulin receptors?
• 6. Effects on pancreatic βcells

• 1. Offspring risk of

metabolic disorders

“Exposure of mothers to HFD exclusively during the lactation phase exerts the strongest effects on alterations in energy and glucose homeostasis in offspring.”

• 2. Offspring hypothalamic circuits



ARC mRNA expression of POMC, AGRP, NPY: no difference



PVN expression of thyrotropine-releasing hormone (TRH): lower



Hypothalamic mRNA expression of inflammatory markers: no difference



ARC neuron cell numbers: no difference



POMC processing to αMSH: no difference



POMC neuron spontaneous firing rate, resting membrane potential, and synaptic input: no difference

• 2. Offspring hypothalamic circuits



ARC mRNA expression of POMC, AGRP, NPY: no difference



PVN expression of thyrotropine-releasing hormone (TRH): lower



Hypothalamic mRNA expression of inflammatory markers: no difference



ARC neuron cell numbers: no difference



POMC processing to αMSH: no difference



POMC neuron spontaneous firing rate, resting membrane potential, and synaptic input: no difference

Thyrotropine releasing hormone (TRH)

α-MSH exerts anorexigenic functions in part by upregulating TRH

TRH regulation

“Offspring of undernourished mothers share several metabolic impairments with offspring with

• bese mothers…and decreased

pancreatic parasympathetic activity” But – no detected differences in classical markers for inflammation

• 3. ARC neuron projections to

downstream sites in hypothalamus

 Three main downstream sites

for projections from ARC:

 PVN – posterior (preautonomic)  PVN – anterior (neuroendocrine,

including TRH)

 DMH  LA

 Robust reductions in αMSH and

AgRP neuronal fiber densities in NCD/HFD offspring in all areas

Axonal fiber densities

• 4. Role of POMC insulin signaling

HFD during lactation Increased glucose and insulin in milk Hyperinsulin- emia in

• ffspring at 3

weeks

IR POMC neuron

Role of POMC insulin signaling on predisposition to metabolic disorders

NCD/NCD vs. NCD/HFD

 Body weight: no difference  Adiposity: higher in NCD/HFD  Leptin levels: higher in NCD/HFD  Insulin sensitivity: impaired in NCD/HFD

(insulin tolerance test and HOMA-IR)

NCD/HFD vs. NCD/HFD/POMC IR ko

 No differences  Except IR knockout rescues glucose

intolerance

?

POMC insulin receptor knockout during lactation improves insulin signaling What other players? Leptin – role in gestational diet

Effects of POMC IR knockout

• 5. Effect of POMC IR on axonal

projections to PVN

αMSH axonal projections

 PVN anterior: no difference  PVN posterior: rescue  DMH: no difference  LA: no difference

AgRP axonal projections

 PVN anterior: no difference  PVN posterior: no difference  DMH: no difference  LA: no difference

Hyperinsulinemia during lactation impairs POMC axonal growth to posterior (preautonomic) PVN

• 6. Effect of POMC IR knockout on

pancreatic βcells

Vesicular ACh transporter (vAChT)

 vAChT buttons per islet area: greatly

reduced by NCD/HFD offspring

 Rescued by POMC IR knockout  Glucose stimulated insulin secretion

decreased in NCD/HFD offspring

 Rescued by POMC IR knockout  (But impairments not seen with L-

arginine stimulation, GLP-1, or FFA)

 No difference in βcell mass or islet size

Summary

 Lactation is most sensitive dietary period for offspring predisposition to metabolic

disorders

 HFD during lactation impairs ARC innervation of intrahypothalamic target areas

(recall mouse cross fostering experiments)

 Critical period: not reversible by reverting to normal chow after 8 weeks  POMC IR signaling not critical under normal development conditions  POMC IR knockout rescue of second order axonal projections is site-specific to

posterior PVN

 Other mechanisms must contribute to impaired axonal projections to other areas

(leptin, FFAs, et al.)

 HFD-induced reduction of pancreatic vagus innervation rescued by POMC IR

knockout